Identification of immunogenic mutant peptides using genomic, transcriptomic and proteomic information

Patent metadata

Field	Value
Publication number	US-10564165-B2
Application number	US-201514850864-A
Country	US
Kind code	B2
Filing date	Sep 10, 2015
Priority date	Sep 10, 2014
Publication date	Feb 18, 2020
Grant date	Feb 18, 2020

Abstract

The present disclosure provides methods of identifying a disease-specific immunogenic peptide through a series of selection steps. Immunogenic epitopes identified by methods of the present disclosure are applicable for use in peptide-based immunotherapy, preferably cancer therapy. Furthermore, the methods of the present disclosure may be performed in a high-throughput manner and serve as a means of personalized vaccine development and therapy. Also provided are compositions of immunogenic peptides as well as methods of treatment comprising said compositions.

First claim

What is claim is:

1. A method of identifying a disease-specific immunogenic mutant peptide from a disease tissue in an individual, comprising:
(a) obtaining a first set of variant-coding sequences based on the genomic sequences of the disease tissue in the individual, each variant-coding sequence of the first set having a sequence variation compared to a reference sample;
(b) selecting a second set of expression variant-coding sequences from the first set based on transcriptomic sequences of the disease tissue in the individual;
(c) selecting a third set of epitope variant-coding sequences from the second set based on predicted ability of the peptides encoded by the second set to bind to an MHC class I molecule (MHCI);
(d) obtaining a plurality of peptides that are bound to an MHCI from the disease tissue;
(e) subjecting the MHCI-bound peptides to mass spectrometry-based sequencing,
wherein mass spectrometry-based sequencing comprises identifying MHCI-bound peptides based on transcriptomic sequence information of the disease tissue; and

(f) correlating the mass spectrometry-derived sequence information of the MHCI-bound peptides with the third set of epitope variant-coding sequences, thereby identifying the disease-specific immunogenic mutant peptide.

2. The method of claim 1 , wherein the obtaining the first set of variant-coding sequences based on genomic sequences of the disease tissue in the individual comprises:
(i) obtaining a set of sequences based on the genomic sequences of the disease tissue in the individual; and
(ii) identifying the first set of variant-coding sequences from the set of sequences,
wherein each variant-coding sequence of the first set of variant-coding sequences comprises a variation in the sequence compared to the reference sample.

3. The method of claim 1 , further comprising synthesizing a nucleic acid encoding a peptide based on the sequence of the identified disease-specific immunogenic mutant peptide.

4. The method of claim 1 , wherein the disease is cancer.

5. The method of claim 1 , wherein the individual is human.

6. A method of stimulating an immune response in the individual of claim 1 with the disease of claim 1 comprising:
(a) identifying according to claim 1 the disease-specific immunogenic mutant peptide from the disease tissue in the individual;
(b) producing a composition comprising a peptide or a nucleic acid encoding the peptide based on the sequence of the identified disease-specific immunogenic mutant peptide; and
(c) administering the composition to the individual.

7. The method of claim 6 , further comprising administering an anti-PD-1 antibody to the individual.

8. The method of claim 6 , further comprising administering to the individual an anti-PD-L1 antibody to the individual.

9. The method of claim 1 , further comprising predicting immunogenicity of peptides identified in step (f).

10. The method of claim 9 , wherein predicting immunogenicity is based on one or more of the following parameters:
(i) binding affinity of the peptide to the MHCI molecule;
(ii) protein level of a peptide precursor containing the peptide;
(iii) expression level of the transcript encoding the peptide precursor;
(iv) processing efficiency of the peptide precursor by an immunoproteasome;
(v) timing of expression of the peptide precursor;
(vi) binding affinity of the peptide to a TCR molecule;
(vii) position of a variant amino acid within the peptide;
(viii) solvent exposure of the peptide when bound to a MHCI molecule;
(ix) solvent exposure of the variant amino acid when bound to a MHCI molecule;
(x) content of aromatic residues in the peptide;
(xi) property of the variant amino acid when compared to the wild type residue; and
(xii) nature of the peptide precursor.

11. The method of claim 10 , wherein the prediction of immunogenicity further comprises HLA-typing analysis.

Assignees

• Genentech Inc

Inventors

• Delamarre Lelia
• Lupardus Patrick
• Mellman Ira
• Yadav Mahesh
• Jhunjhunwala Suchit
• Lill Jennie

Classifications

• G01N33/6878

  in epitope analysis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• G01N33/56977

  HLA or MHC typing · CPC title